While there is agreement that zinc (Zn) deficiency interferes with reproduction in experimental animals, and there is strong evidence that suboptimal Zn status can be an etiological factor in human reproductive disorders particularly when combined with other risk factors, there is a paucity of information concerning the mechanisms by which Zn deficiency acts. This proposal examines potential mechanisms by which maternal and embryonic/fetal Zn deficiency arise, and how this deficiency results in abnormal development and growth and early fetal wastage (death during preimplantation development). We suggest that one mechanism by which this can occur is by Zn-deficiency induced alterations in growth factor metabolism. Thus, we will examine the influence of Zn on the following factors: epidermal growth factor (EGF)/TGFalpha (transforming growth factor alpha), insulin, insulin-like growth factor 1 (IGF I) and II (IGF II). In addition to assessing the effects of Zn deficiency on growth factor metabolism, we will test the hypothesis that an increased amount of cellular oxidative damage is one consequence of fetal Zn deficiency which contributes to fetal pathology. We will use pre- and postimplantation embryo, and cell culture techniques to confirm and extend results we obtain at the whole animal level. Embryo culture systems will allow us to directly study the influence of Zn status on the embryo. In addition to studying the influence of media Zn concentration on in vitro embryonic development, we will investigate the role(s) of the Zn-binding protein metallothionein in embryonic development. This work will initially be done using anti-sense MT-mRNA which we have recently shown affects preimplantation embryonic development. Integration of the information obtained at these individual levels should allow us to adequately test the following hypothesis: 1) Zn deficiency results in abnormal growth factor metabolism in pregnant rats and mice and their conceptus. 2) Embryonic/fetal Zn deficiency is associated with increases in the rate and extent of lipid, DNA, and protein oxidation. These increases contribute to the developmental defects associated with Zn deficiency. 3) Embryonic/fetal Zn deficiency can arise from a primary maternal Zn deficiency and/or from a disruption of normal maternal Zn metabolism elicited secondary to a maternal acute phase response.